The goal of this project is to understand the cellular and molecular mechanisms governing bone growth and mineral metabolism. To understand the molecular and cellular mechanisms governing longitudinal bone growth, the investigators developed several experimental approaches including an in vivo experimental system that allows infusion directly into the growth plate, methods for extracting and analyzing specific mRNA transcripts from growth plate cartilage, and a fetal bone organ culture system. Using these system, the investigators demonstrated that glucocorticoid inhibits longitudinal bone growth by a direct action on the growth plate, and found unexpectedly that glucocorticoid increases growth hormone receptor mRNA in growth plate and liver. The investigators further demonstrated that catch-up growth, which was previously thought to be regulated by a neuroendocrine mechanism, actually results from a mechanism intrinsic to the growth plate. They have provided evidence suggesting that fibroblast growth factors attract vascular and bone cell invasion from the adjacent metaphyseal bone, processes critical for endochondral bone formation. In the area of mineral metabolism, this research group recently demonstrated that activating mutations in the Ca2+-sensing receptor gene cause autosomal dominant and sporadic hypoparathyroidism. Because the Ca2+-sensing receptor is expressed not only in parathyroid cells but also in kidney cells, where it negatively regulates calcium reabsorption, the investigators predicted and experimentally confirmed that patients with these mutations have hypercalciuria even at low serum calcium concentrations. Their findings have important implications for the genetic counseling and choice of therapy for these patients. Current experiments are designed to identify additional mutations, to elucidate the molecular mechanism of activation by expressing the mutated receptors in cell culture, and to further explore the physiological and clinical consequences of these mutations.